EP1011681A1 - Preparation contraceptive orale comportant une premiere phase a base de progestine/oestrogene et une seconde phase a base de progestine - Google Patents

Preparation contraceptive orale comportant une premiere phase a base de progestine/oestrogene et une seconde phase a base de progestine

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Publication number
EP1011681A1
EP1011681A1 EP98944837A EP98944837A EP1011681A1 EP 1011681 A1 EP1011681 A1 EP 1011681A1 EP 98944837 A EP98944837 A EP 98944837A EP 98944837 A EP98944837 A EP 98944837A EP 1011681 A1 EP1011681 A1 EP 1011681A1
Authority
EP
European Patent Office
Prior art keywords
days
combination
levonorgestrel
administered
progestin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98944837A
Other languages
German (de)
English (en)
Inventor
Michael Jay Gast
Original Assignee
American Home Products Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Home Products Corp filed Critical American Home Products Corp
Publication of EP1011681A1 publication Critical patent/EP1011681A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives

Definitions

  • oral contraceptives consist of a combination of a progestin and estrogen that are administered concurrently for 21 days followed either by a 7 day pill free interval or by the administration of a placebo for 7 days in each 28 day cycle.
  • the most important aspects of a successful oral contraceptive product are effective contraception, good cycle control (absence of spotting and breakthrough bleeding and
  • Combination oral contraceptives have traditionally acted by suppression of gonadotropins.
  • progestin component is primarily responsible for contraceptive efficacy through inhibition of ovulation, and other peripheral effects which include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the
  • the estrogenic component intensifies the anovulatory effect of the progestin, and is also important for maintaining cycle control.
  • Levonorgestrel is the biologically active moiety of racemic norgestrel. It is strongly progestational, has no inherent estrogenic activity, is antiestrogenic, and possesses good biologic activity. The contraceptive effects of levonorgestrel are manifested throughout the hypothalamic- pituitary-gonadal-target organ axis.
  • Ethinyl estradiol is the estrogen most frequently used in combination OCs.
  • the dosage of EE in marketed OC formulations has been steadily reduced from that found in earlier OCs.
  • Thromboembolic mortality decreased when the amount of synthetic estrogen in OC formulations was reduced from 100 ⁇ g to 50 ⁇ g.
  • a significant reduction in fatal myocardial infarctions was reported for women using OCs with 30 ⁇ g of EE rather than 50 ⁇ g of EE. [Meade TW. Br Med J 280:1157 (1980)].
  • progestin/estrogen combination is administered either as a fixed dosage combination (monophasic) or as biphasic or triphasic regimens in which the dosage of the combination is varied either once or twice throughout the menstrual cycle.
  • the progestin/estrogen combination is typically administered for 21 days followed by either a 7-day pill free period or the administration of a non-contraceptive placebo (or iron supplement) for 7 days.
  • 3-ketodesogestrel (3-KDSG), desogestrel (DSG), levonorgestrel (LNg), gestodene (GTD), norgestrel (NG), and norethindrone (NE) are typically used as the progestin while ethinyl estradiol (EE); 17 ⁇ -estradiol, and mestranol are typically the estrogenic components.
  • De Jager discloses 22-30 day bridged regimens consisting of the administration of 20-22 (preferrably 21) days of a progestin/estrogen combination followed by 2-10 (preferrably 7) days of a progestin.
  • Specifically disclosed regimens include (a) a combination of 150 ⁇ g DSG and 2.0 mg 17 ⁇ -estradiol for 21 days, followed by 30 ⁇ g desogestrel for 7 days; (b) a combination of 150 ⁇ g DSG and 30 ⁇ g EE for 21 days, followed by 30 ⁇ g desogestrel for 7 days; (c) a combination of 50 ⁇ g DSG and 3 mg 17 ⁇ -estradiol for 7 days, followed by a combination of 150 ⁇ g DSG and 2 mg 17 ⁇ -estradiol for 14 days, followed by 30 ⁇ g DSG for 7 days; (d) a combination of 50 ⁇ g DSG and 35 ⁇ g EE for 7 days, followed by a combination of 150 ⁇ g DSG and 30 ⁇ g EE for 14 days, followed by 30 ⁇ g DSG for 7 days; (e) a combination of 50 ⁇ g DSG and 3 mg 17 ⁇ -estradiol for 7 days, followed by a combination of 100 ⁇ g DSG and 2 mg 17
  • Endrikat discloses bridged regimens consisting of the squential administration of an ovulation inhibiting dose of a progestin for at least 28 days and a natural estrogen during the last 5-10 days of the at least 28 day sequential administration.
  • a preferred contraceptive kit consists of 28 daily dosage units with a first phase having 18-23 daily dosage units of a progestin and a second phase having 5-10 daily dosage units of a prigestin in combination with a natural estrogen.
  • Specific disclosed regimens include: (a) administration of 100 ⁇ g LNg for 28 days, with 2.5 mg 17 ⁇ -estradiol concomitantly adminsistered for the last 10 days of the 28-day administration; (b) administration of 100 ⁇ g LNg for 28 days, with 2.5 mg 17 ⁇ -estradiol concomitantly adminsistered for the last 8 days of the 28-day administration; (c) administration of 100 ⁇ g LNg for 56 days, with 2.5 mg 17 ⁇ - estradiol concomitantly adminsistered for the last 10 days of the 56-day administration; (d) administration of 100 ⁇ g LNg for 84 days, with 2.5 mg 17 ⁇ -estradiol concomitantly adminsistered for the last 10 days of the 84-day administration; and equivalent regimens using 75 ⁇ g GTD as the progestin.
  • Erlich discloses sequential contraceptive regimens consisting of the administration of an estrogen which effects a disturbance of follicle stimulation, followed by the administration of a combination of a progestin/estrogen in a dose at least adequate to inhibit ovulation.
  • the regimen is administered for a total of 28 days per cycle. It is preferred that the estrogen is administered for 5-14 days per cycle and the progestin/estrogen combination is administered for 23-14 days per cycle, so that the total administration is for 28 days per cycle.
  • Specific regimens include (a) 4 mg estradiol for 7 days followed by 21 days of the combination of 1 mg norethisterone acetate and 4 mg estradiol; (b) 2 mg estradiol valerate for 7 days followed by 21 days of the combination of 2 mg chlormadinone acetate and 4 mg estradiol valerate; and (c) 20 ⁇ g EE followed by 18 days of the combination of 150 ⁇ g LNg and 20 ⁇ g EE.
  • Regimen (c) in Erlich provides a total steroidal load of 2.7 mg of LNg and 560 ⁇ g EE per 28 day cycle.
  • Lachnit (PCT Publication WO 95/26730) discloses bridged regimens consisting of the administration of a combination of a progestin/estrogen combination (50 - 125 ⁇ g LNg and 10 - 40 ⁇ g EE) for the first 23-24 days of the menstrual cycle followed by the administration of an estrogen (2 - 40 ⁇ g EE) for 4-10 days for a total administration of at least 28 days per cycle.
  • the use of 100 - 300 ⁇ g drospirenone and 10 - 40 ⁇ g EE as the 23-24 day progestin/estrogen combination is disclosed.
  • Lachnit also discloses a triphasic plus bridging regimen (4-9 days, 4-9 days, 9-13 days, and 28 days for the three phases and estrogen phase, respectively) in which a combination of 50 ⁇ g LNg and 20 ⁇ g EE are administered in the first phase, a combination of 75 ⁇ g LNg and 25 ⁇ g EE are administered in the second phase, a combination of 100 ⁇ g LNg and 20 ⁇ g EE are administered in the third phase, and 10 ⁇ g EE is administered in the estrogen phase.
  • Other progestins disclosed include GTD, DSG, 3-KDSG, DRSP, cyproterone acetate, norgestimate, and norethisterone.
  • Moore discloses bridged triphasic regimens consisting of the administration of a combination of 10 - 50 ⁇ g LNg and 5 - 20 ⁇ g EE from days 1-7 of the menstrual cycle; of 50 - 75 ⁇ g LNg and 5 - 20 ⁇ g EE from days 8-14 of the menstrual cycle; of 75 - 125 ⁇ g LNg and 5 - 20 ⁇ g EE from days 15-21 of the menstrual cycle; and 5 - 20 ⁇ g EE from days 22-28 of the menstrual cycle.
  • Upton Upton (EP Patent Specification 253,607 Bl) teaches the use of low dose progestin/estrogen combinations for combined hormone replacement therapy and contraception in climacteric women.
  • Climacteric women are defined in Upton as pre- menopausal women around 40 years of age whose hormone levels are waning. The climacteric woman still ovulates (albeit may have irregular ovulation), but she still experiences many of the symptoms of the hypoestrogenic menopausal woman, such as insomnia, hot flushes, and irritability.
  • Upton teaches the administration of a 23-26 day monophasic regimen of progestin/estrogen followed by a pill free or placebo interval of 2-5 days; with 24 days of progestin/estrogen administration followed by a 4-day pill free or placebo administration being preferred.
  • Upton teaches the use of a progestin selected from 25 - 100 ⁇ g LNg, 10 - 70 ⁇ g GTD, 25 - 100 ⁇ g DSG, 25 - 100 ⁇ g 3- KDSG, and 85 - 350 ⁇ g NE used in combination with an estrogen selected from 500 - 2000 ⁇ g 17 ⁇ -estradiol, 8 - 30 ⁇ g EE, and 15 - 60 ⁇ g mestranol.
  • Upton Based on relative potencies, Upton teaches that a dose of 75 ⁇ g LNg is equivalent to 35 ⁇ g of GTD, 75 ⁇ g of 3-KDSG or DSG, and 250 ⁇ g NE and that a dose of 1000 ⁇ g of 17 ⁇ -estradiol is equivalent to a dose of 15 ⁇ g EE and 30 ⁇ g mestranol. Upton also teaches that NG may be substituted for LNg, but at twice the dose.
  • the Bergink discloses a 24 day triphasic combination regimen in which the first 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to 100 ⁇ g DSG and an estrogen at a daily dosage equivalent to 25 ⁇ g EE, the second 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to 125 ⁇ g DSG and an estrogen at a daily dosage equivalent to 20 ⁇ g EE, and the third 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to 50 ⁇ g DSG and an estrogen at a daily dosage equivalent to 20 ⁇ g EE. It is preferred that the three phases be 8 days each. Following the 24 day contraceptive steroid administration, a placebo may be administered for 4 days, the 4 day interval may be pill free, or a progestin at a dosage equivalent to 25-35 ⁇ g DSG may be administered.
  • This invention provides a progestin bridged combination progestin/estrogen oral contraceptive regimen for females of child-bearing age that provides effective contraception, good cycle control, and minimal side effects while greatly reducing the total contraceptive steroid administered per 28-day cycle.
  • the low dose progestin/estrogen combination is administered for 23- 25-days per cycle followed by the administration of a progestin for the remaining 3-5 days of the cycle.
  • Administration of the contraceptive progestin/estrogen combination is begun on the first day of menses (day 1), and continued for 23-25 consecutive days.
  • this invention provides a method of contraception which comprises administering to a female of child bearing age a combination of a progestin at a daily dosage equivalent in progestational activity to 40-150 ⁇ g levonorgestrel and an estrogen at a daily dosage equivalent in estrogenic activity to 10-20 ⁇ g ethinyl estradiol for 23-25 days beginning on day 1 of the menstrual cycle.
  • a progestin at a daily dosage equivalent to 10-100 ⁇ g levonorgestrel is administered for 3-5 days.
  • the total administration during each cycle is 28 days.
  • progestins include, but are not limited to levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethisterone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, and drospirenone. It is more preferred that the progestin is levonorgestrel. When levonorgestrel is used as the progestin during the first 23-25 days of the cycle, it is preferred that the daily dosage of levonorgestrel is 30-150 ⁇ g, with 50-100 ⁇ g being more preferred, and 90 ⁇ g being most preferred.
  • the daily dosage be 10-100 ⁇ g, with 20-50 ⁇ g levonorgestrel being more preferred, and 37.5 ⁇ g most preferred.
  • Preferred dosages of the preferred progestins are provided in the table below.
  • Levonorgestrel 30-150 ⁇ g 10-100 ⁇ g
  • Preferred estrogens include, but are not limited to ethinyl estradiol; 17 ⁇ - estradiol; conjugated estrogens, USP; estrone or a salt thereof; and mestranol; with ethinyl estradiol being more preferred.
  • ethinyl estradiol is used as the estrogen the preferred daily dosage is 10-20 ⁇ g, with 15 ⁇ g being more preferred.
  • 17 ⁇ - estradiol is used as the estrogen, it is preferred that the daily dosage of 17 ⁇ -estradiol is 1-3 ⁇ g.
  • Preferred salts of estrone include, but are not limited to the sodium and piperate salt.
  • the daily dosage is 0.3-5 mg, with a daily dose of 1.25 mg conjugated estrogens, USP being equivalent to a daily dose of 15 ⁇ g ethinyl estradiol. It is preferred that the progestin/estrogen combination be administered for 24 days beginning on day 1 of the menstrual cycle, and following this 24-day period, it is preferred that the progestin be administered for 4 days.
  • the following daily dosages of a combination of levonorgestrel and ethinyl estradiol are preferred for contraception when administered for 23-25 consecutive days beginning on the first day of menses, followed by the administration of levonorgestrel for 3-5 days.
  • the total administration during each cycle is 28 days.
  • the combination progestin/estrogen contraceptive be administered in unit dosage form i.e., tablet or pill, with each unit providing the entire daily dosage. It is preferred that the progestin and estrogen are admixed together in the same dosage unit. Such dosage units can be prepared by conventional methodology that is well known to one skilled in the art. In each dosage unit, the contraceptively active progestin and estrogen are combined with excipients, vehicles, pharmaceutically acceptable carriers, and colorants. For example, the following illustrates an acceptable composition of a contraceptive progestin/estrogen combination of this invention.
  • the progestin be administered in unit dosage form i.e., tablet or pill, with each unit providing the entire daily dosage.
  • unit dosage form i.e., tablet or pill
  • each unit providing the entire daily dosage.
  • dosage units can be prepared by conventional methodology that is well known to one skilled in the art.
  • the estrogen is combined with excipients, vehicles, pharmaceutically acceptable carriers, and colorants.
  • the following illustrates an acceptable estrogen composition of this invention.
  • This invention also provides a contraceptive kit adapted for daily oral administration which comprises a total of 28 separate dosage units.
  • this kit 23-25 dosage units each consisting of a combination of progestin at a daily dosage equivalent in progestational activity to 30-150 ⁇ g levonorgestrel and an estrogen at a daily dosage equivalent to 10-20 ⁇ g ethinyl estradiol.
  • the remaining 3-5 dosage units contain an progestin at a daily dosage equivalent to 10-100 ⁇ g levonorgestrel.
  • the daily dosage arrangements are preferably arranged in a blister pack or in a dial pack type tablet dispenser. Specific referred progestins and estrogens and the specifically preferred dosages of each combination dosage unit are described above.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un procédé de contraception consistant à administrer à une femme en âge de procréer, pendant 23-25 jours à partir du premier jour du cycle menstruel, une combinaison de progestine à une posologie quotidienne équivalente à 30-150 νg de lévonorgestrel et d'un oestrogène à une posologie quotidienne équivalente à 10-20 νg d'éthinyloestradiol, puis à administrer pendant 3-5 jours une progestine à une posologie quotidienne équivalente à 10-100 νg de lévonorgestrel, la durée totale d'administration étant de 28 jours par cycle menstruel.
EP98944837A 1997-09-12 1998-09-09 Preparation contraceptive orale comportant une premiere phase a base de progestine/oestrogene et une seconde phase a base de progestine Withdrawn EP1011681A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US92853097A 1997-09-12 1997-09-12
US928530 1997-09-12
PCT/US1998/018850 WO1999013882A1 (fr) 1997-09-12 1998-09-09 Preparation contraceptive orale comportant une premiere phase a base de progestine/oestrogene et une seconde phase a base de progestine

Publications (1)

Publication Number Publication Date
EP1011681A1 true EP1011681A1 (fr) 2000-06-28

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ID=25456367

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98944837A Withdrawn EP1011681A1 (fr) 1997-09-12 1998-09-09 Preparation contraceptive orale comportant une premiere phase a base de progestine/oestrogene et une seconde phase a base de progestine

Country Status (6)

Country Link
EP (1) EP1011681A1 (fr)
JP (1) JP2001516720A (fr)
CN (1) CN1270521A (fr)
AU (1) AU759925B2 (fr)
CA (1) CA2301162A1 (fr)
WO (1) WO1999013882A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001030355A1 (fr) * 1999-10-25 2001-05-03 Laboratoire Theramex Medicament contraceptif a base d'un progestatif et d'un estrogene et son mode de preparation
FR2754179B1 (fr) 1996-10-08 1998-12-24 Theramex Nouvelle composition hormononale et son utilisation
WO2003041719A1 (fr) * 2001-11-15 2003-05-22 Pantarhei Bioscience B.V. Procede de contraception chez des femelles de mammiferes, et kit pharmaceutique correspondant
BRPI0214716B8 (pt) 2001-12-05 2021-05-25 Teva Womens Health Inc kit, preparos, e uso de estrogênio e progestina na fabricação de um medicamento para uso na prevenção de gravidez
CA2478165A1 (fr) * 2002-03-11 2003-09-25 Janssen Pharmaceutica N.V. Schemas posologiques contraceptifs uniquement a base de progestogene inhibant l'activite sulfatase
JP2005519963A (ja) * 2002-03-11 2005-07-07 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 長期サイクルのエストロゲンおよびスルファターゼ阻害プロゲストゲン避妊レジメン
WO2003077925A1 (fr) * 2002-03-11 2003-09-25 Janssen Pharmaceutica N.V. Regime contraceptif continu a base de progestogene inhibiteur de la sulfatase
US20070111975A1 (en) 2004-10-07 2007-05-17 Duramed Pharmaceuticals, Inc. Methods of Hormonal Treatment Utilizing Ascending-Dose Extended Cycle Regimens
CN104546870B (zh) * 2015-01-27 2018-01-12 唐凡兰 一种避孕药

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0368373A1 (fr) * 1988-10-13 1990-05-16 Akzo Nobel N.V. Préparation contraceptive multiphase
DE19549264A1 (de) * 1995-12-23 1997-06-26 Schering Ag Verfahren und Kit zur Kontrazeption

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9913882A1 *

Also Published As

Publication number Publication date
CN1270521A (zh) 2000-10-18
AU759925B2 (en) 2003-05-01
AU9228698A (en) 1999-04-05
CA2301162A1 (fr) 1999-03-25
WO1999013882A1 (fr) 1999-03-25
JP2001516720A (ja) 2001-10-02

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